This project is designed to investigate the therapeutic effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, on the endogenous neuroplasticity that occurs after traumatic brain injury (TBI) in young adult male Wistar rats. The final goal is to develop a safe and efficacious treatment for TBI, which will reduce neurological defects. Young adult male rats will be subjected to TBI and then treated orally with different doses of simvastatin at various times after TBI. Spatial learning of the rat will be measured using the Morris Water Maze Test. Neurogenesis in the ipsilateral dentate gyrus will be evaluated (Specific Aim 1). The efficacy of simvastatin treatment will be tested and determined based on functional testing and the changes in neurogenesis. In Specific Aim 2, we will employ immunohistochemical staining, laser cofocal microscopy and enzyme- linked immunosorbent assay (ELISA) to study the dynamic changes of neurogenesis, astrogliogenesis and oligogliogenesis in the dentate gyrus from day 15 to 12 months after TBI. Our observations will provide detailed profiles of the effect of simvastatin treatment on neurogenesis, astrogliogenesis and oligogliogenesis after TBI (A). The microenvironment that regulates neurogenesis in the dentate gyrus will be further investigated after TBI and simvastatin treatment, including angiogenesis, cellular (astrocytes and oligodendrocytes) and molecular (growth factors) regulation (B), as well as intravascular thrombosis and vascular structure (C). These studies will provide insight into the underlying changes in the injured brain induced by statin treatment that contributes to its neurorestorative effect. The ultimate goal of this application is to develop a new treatment for TBI using a statin that will enhance endogenous neuroplasticity in the dentate gyrus, especially neurogenesis, and thereby improving spatial learning after TBI. [unreadable] [unreadable] [unreadable]